Age-related macular degeneration (AMD) is a complex disease in which the contributions of many genetic and environmental factors are confounding. No single risk factor can predict AMD reliably in humans, and similarly, no single intervention in animals is able to produce a robust AMD model. The disease manifests as the more common dry form, and the less common, but more devastating wet form. Of the proposed mechanisms for dry AMD, most evidence exists for dysregulated systemic complement activation, predominantly due to polymorphisms in complement factor H, or CFH and a cardiovascular risk profile. The recent discovery of a polymorphic variant of HTRA Serine Peptidase 1 (HTRA1) as a risk factor for wet AMD implicates an entirely different mechanism (abnormal matrix metabolism and TGF-2 signaling) underlying the wet form of AMD. The ultimate intent of this proposal is to create an early onset, comprehensive AMD ocular phenotype in mice for future use in therapeutic trials. Our central hypothesis is that combining genetic and environmental risk factors can induce more comprehensive AMD-like pathology in mice. First, we will test the hypothesis that combined complement dysregulation and lipid-induced systemic inflammation can worsen AMD-like pathology. In Aim 1, we will breed mice lacking one or more genes conferring AMD risk in humans (CFH) or mice (ApoE, Ccr2) and expose these to normal or high fat high cholesterol diets. The effects of genotype and diet upon development of ocular pathology and biomarkers of inflammation will be compared. Next, we will explore the role of HTRA1 overexpression in wet AMD. In Aim 2, we will generate a Cre-Lox inducible HTRA1 knockin mouse that overexpresses human HTRA1 in a) endothelium or b) in the majority of tissues. This aim will test the hypothesis that HTRA1 overexpression can induce choroidal neovascularization typical of wet AMD. Experiments in Aim 1 will provide insight into whether complete CFH-/- deletion can result in AMD-like pathology when combined with additional genetic and dietary risk factors. In Aim 2, we will thoroughly test the hypothesis that increased expression of HTRA1 promotes CNV. The long term goal of this study is to combine the models developed in Aim1 and 2 to provide a comprehensive mouse model of progressive (i.e dry to wet) AMD in humans. Age-related macular degeneration is the predominant cause of vision loss in adults over 65. Lack of effective treatment stems from both the complexity of the disease, and lack of good animal models in which to study it. This proposal offers the potential to provide a robust early onset mouse model for therapeutic testing. These experiments also provide insight into how modifiable variables (diet) interact with predisposing genetic burden to create AMD pathology. Understanding these relationships will enhance the capacity of the clinician to council at-risk patients.